Human red blood cell (erythrocyte) diseases, including anemia and malaria, pose a huge burden for the human race. Our understanding of these diseases is rather limited. For example, while the genetic cause of sickle cell diseases (SCD) and the positive selection of them imposed by malaria infection have been long established, much remains to be learned about how SCD erythrocyte phenotypes contribute to diverse clinical manifestations and to altered interaction with malaria parasites. Human mature erythrocytes are thought to lack most RNA expression. With a procedure capturing small-sized RNAs, we have found that human mature erythrocytes still possess abundant and diverse microRNAs (miRNAs), a class of 21-23 nucleotide non-coding RNA with important regulatory functions. Given the potential regulatory roles of miRNAs during erythropoiesis, the erythrocyte miRNA pool is likely to contain important biological information, indicate developmental history, and show biological phenotypes of erythrocytes. The analysis of miRNA expression with miRNA microarrays indeed reveals a dramatic difference between normal and SCD erythrocytes. Erythrocyte miRNAs may also play a functional role in the mature erythrocyte. Several miRNAs have been found to be translocated into malaria parasites during intraerythrocytic infection. These transferred miRNAs disrupt the growth and replication of malaria parasites. We hypothesize that the altered miRNA expression in SCD erythrocytes compared to normal erythrocytes may contribute to their decreased susceptibility to malaria infection. In this proposal, we plan to apply genomic tools and advanced bioinformatics to examine the role of miRNAs as genetic determinants of SCD phenotypes and malaria susceptibility. In the first specific aim, we will identify erythrocyte miRNAs whose expression can distinguish between normal erythrocytes, different SCD subtypes, and other anemia disorders. The identification of these miRNAs will hold diagnostic value for anemia disorders and lead to fresh insights into relevant underlying pathophysiological mechanisms. In the second aim, we will determine whether the differences in miRNA composition among different types of erythrocytes contribute to their differing susceptibility to malaria infection. The completion of these experiments will result in a better understanding of the role of miRNAs in determining erythrocyte phenotypes in hemoglobinopathies and infectious diseases as well as provide better therapeutic strategies for SCD and malaria infection. PUBLIC HEALTH RELEVANCE: In this proposal titled "The Genomic Analysis of Erythrocyte microRNA in Sickle Cell Diseases", I plan to use novel genomic tools and advanced bioinformatics to analyze the erythrocyte microRNA contents in sickle cell diseases. We expect that our study will determine the role of erythrocyte microRNAs in informing the erythrocyte phenotypes and clinical manifestations of sickle cell diseases. We will also define the role of erythrocyte microRNA in determining the in vitro susceptibility to Plasmodium falciparum among the normal and sickle erythrocytes.